Diels-Alder reaction factors favoring

When both the 1,3-dipoIe and the dipolarophile are unsymmetrical, there are two possible orientations for addition. Both steric and electronic factors play a role in determining the regioselectivity of the addition. The most generally satisfactory interpretation of the regiochemistry of dipolar cycloadditions is based on frontier orbital concepts. As with the Diels-Alder reaction, the most favorable orientation is that which involves complementary interaction between the frontier orbitals of the 1,3-dipole and the dipolarophile. Although most dipolar cycloadditions are of the type in which the LUMO of the dipolarophile interacts with the HOMO of the 1,3-dipole, there are a significant number of systems in which the relationship is reversed. There are also some in which the two possible HOMO-LUMO interactions are of comparable magnitude. 

Grieco has used his aqueous imnicmium Diels-Alder procedure to effect a number of intramolecular reactions. In one case, diene aldehyde (83) was treated with ammonium chloride to afford a 2.2 1 mixture of isomeric Diels-Alder adducts (87) and (85) (Scheme 10). Since intermediate immonium ions (84)/(86) cannot participate in secondary orbital effects as is the case with A-acyl imines (c/. 80), these results are probably due to steric factors. It was suggested that adduct (85) derives from conformation (84) and adduct (87) comes from (86). Conformer (84) is favored since there is a severe eclipsing of Ha b in (86). A more detailed account of the stereochemical aspects of intramolecular Diels-Alder reactions can be found in Chapter 4.4. 

C2-chiral bidentate fluoroarylphosphinite ligands, efficiently catalyze the asymmetric Diels-Alder reaction between enals and 1,3-dienes [36], Electronic factors apart, the catalyst creates a chiral contour that favors enal coordination, and subsequently this was extended to Ru Lewis acids [37]. These are stable at room temperature, and can be recycled almost quantitatively after the reaction. The immediate catalyst precursor, Ru(Cp)(BIPHOP-F)I is readily available via a one-pot synthesis from Ru3(CO)i2. Although the Ru-catalysts were at first not quite as active as the Fe analogues and produced lower asymmetric induction than the Fe analogues, structural data showed the way to improve the situation (Scheme 10.21). 

The preceding discussion is not meant to imply that stereo electronic effects alone are responsible for determining diastereoselection in the Diels-Alder reaction. Indeed, examples of reactions that do not conform to the endo rule abound, and these cases are not easily explained without invoking alternative hypotheses. For instance, it has been demonstrated that 1,1-disubstituted dien-ophiles can favor formation of the exo product with cyclopentadiene, sometimes to the complete exclusion of the electronically favored endo isomer [19]. There appears to be subtle interplay between steric and electronic factors, as simply switching the diene to cyclohexadiene or an acyclic diene results in a turnover in selectivity to favor the endo isomer. While the exact source of stereocontrol for a given cycloaddition is still a source of debate, this review will emphasize the practical ramifications of diastereoselection, namely, prototypical dienophiles such as a-methacrolein and a-bromoacrolein can be relied on to deliver exo cycloadducts preferentially with cyclopentadiene endo otherwise), while acrylate, crotonate, and cinnamate-derived dienophiles will generally favor the endo tran-... 

When both 1,3-dipole and dipolarophile are unsymmetrical, two products are possible. The formation of major product can be predicted by consideration of their TSs. The most stable TS will provide the major product. The stabihty of the TS is controlled by both electronic and steric factors. Therefore, the regioselectivity of a 1,3-DPCA reaction is determined by the steric and electronic properties of the substituents attached to 1,3-dipole and dipolarophile. The FMO theory may also be applied to analyze the regioselectivity of 1,3-DPCA reaction [107]. A relatively stronger donor-acceptor interaction between HOMO and LUMO and lowest dipole moment favors the TS. The HOMO and LUMO of a 1,3-dipole are similar to that of a diene in a Diels-Alder reaction. The interactions of HOMO or LUMO of a dipole with a LUMO or HOMO of a dipolarophile depend on their electron donor and electron acceptor property. The orbital interactions of HOMO and LUMO of dipole and dipolarophile are shown in Fig. 3.11. 

Concerted reactions are commonly used to join carbons. For example, the Diels-Alder reaction is the formation of a cyclohexene from a diene and an alkene. Usually the alkene is rendered electrophilic by conjugation with a carbonyl group, and the diene may be rendered nucleophilic by electron-donating substituents. In the case shown in Equation 7.38 the alkene is further electron depleted by association with a Lewis acid [64], a common technique for accelerating Diels-Alder reactions. In some cases, the alkene is nucleophilic and the diene is electrophilic as in Equation 7.39 [65]. Examples of this sort are called reverse-electron-demand Diels-Alder reactions. It is important to point out here that the concerted reactions differ from the foregoing in that no carbanion or cation intermediate is involved, and in many cases, electrophilic and nucleophilic factors are not present, as in the very favorable dimerization of cyclopentadiene. These reactions are covered in more detail in Chapter 5. 

Facial selectivity in Diels-Alder reactions has also been studied using theoretical methods. Poirier et al. have studied reactions of ethylene with 5-substituted cyclopenta-dienes (12) and have shown that the major factor responsible for determining the facial selectivity is the deformation of the addends at the transition states, and not the direct interaction between the diene and the dienophile. For reactions between cyclopentadiene and chiral butenolides (13) the most favorable diastereoisomer corresponds to the attack of the diene at the less sterically hindered face of the lactone. Steric interaction between the addends is also reflected in geometry distortions at the transition states. 

In general, reaction of (110) with a wide variety of dienes was quite satisfactory (67JOC330). Only the most unreactive dienes such as hexachl-orocyclopentadiene and hexachlorobutadiene failed to react under the conditions employed. The chief limitation of this dienophile is that the mixture cannot be heated to force reaction without the decomposition of (110). Another important observation was the strong, almost complete preference for undergoing the Diels-Alder-type addition even when other reactions are possible. This may be attributed to the two favorable factors of cis configuration and electron deficiency that are exhibited by 4-phenyl-1,2,4-triazoline-3,5-dione. 

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